Mechanisms Underlying Impaired Nephrogenesis in Prematurity

Chronic kidney disease is a devastating illness characterised by a progressive decline in kidney function that is associated with increased morbidity and mortality in 10% of the global population. Patients with end-stage kidney disease require a kidney transplant or life-long dialysis yet there are not enough organs to meet demand and dialysis has a 5-year survival rate worse than many cancers. While diabetes, obesity and hypertension are the major drivers of chronic kidney disease, being born with a low number of filtration units (nephrons) increases the risk of chronic kidney disease 3-5 fold. This is of particular concern for preterm babies, who are born with low nephron number. In world-leading research Volovelsky and Combes have previously demonstrated that genetic and nutritional manipulation of nephron stem/progenitor cells in mice can increase or rescue nephron number at birth. These breakthroughs enable a new possibility to increase nephron number in at-risk individuals to protect against chronic kidney disease. In this proposal, we seek support to precisely characterise how prematurity affects nephron number, and to test interventions in animal models that may protect the developing kidney from the effects of prematurity. If successful, this project will pioneer a new therapeutic strategy to mitigate the impact of prematurity on kidney development and disease. Our research is likely to benefit the development of other essential organs impacted by prematurity and may provide new avenues to promote tissue regeneration and repair in adulthood.